Background Burden of disease studies intend to improve public health decision-making and to measure social and economic impact in population. The objective of this study was to describe the burden of acute respiratory infections (ARI) in Ecuador between 2011 and 2015. Methods Five-year period morbidity and mortality data available from national agencies of statistics was analyzed to estimate the burden of disease attributable to acute respiratory infections. Cases and deaths registered were grouped according to their ICD-10 code into three diagnostic groups: Acute upper respiratory infections (J00-J06), Influenza and pneumonia (J09-J18), and Bronchitis and other acute lower respiratory infections (J20-J22, J85, J86). Disability-adjusted life years stratified by diagnostic and age group were calculated using the “DALY” package for R. The productivity loss in monetary terms was estimated using the human capital method. Results Over the 5-year period studied there were a total of 14.84 million cases of acute respiratory infections, with 17 757 deaths reported (0.12%). The yearly burden of disease ranged between 98 944 to 118 651 disability-adjusted life years, with an estimated average loss of productivity of US$152.16 million (±19.6) per year. Approximately 99% of the burden can be attributed to years life lost due to premature mortality in population under 5 years old and over 60 years-old. Conclusions The burden of acute respiratory infections remained steady during the analyzed period. Evidence-based prevention and control policies to tackle acute respiratory infections in Ecuador should focus on the population at extreme ages of life.

The burden of acute respiratory infections in Ecuador 2011-2015

May
The burden of acute respiratory infections in Ecuador 2011-2015
Wilson Chicaiza-Ayala 0 2 3
Aquiles R. HenrÂõquez-Trujillo 0 2 3
Esteban Ortiz-Prado 0 1 2 3
Richard W. Douce 0 3
Marco Coral-Almeida 0 2 3
0 Current address: Faculty of Health Sciences, Via Nayon S/N Universidad de Las AmeÂ ricas , Quito , Ecuador
1 Department of Medicine and Center for Global Health and Translational Science, State University of New York Upstate Medical University , Syracuse , New York, United States of America, 3 Department of Internal Medicine, Lakeland Health Care , St. Joseph, Michigan , United States of America
2 OneHealth Research Group, Faculty of Health Sciences, Universidad de Las AmeÂ ricas , Quito , Ecuador
3 Editor: Oliver Schildgen, Kliniken der Stadt KoÈln gGmbH , GERMANY
Background Burden of disease studies intend to improve public health decision-making and to measure social and economic impact in population. The objective of this study was to describe the burden of acute respiratory infections (ARI) in Ecuador between 2011 and 2015.
-
Data Availability Statement: Data are available at
the public database from the Instituto Nacional de
EstadÂõsticas y Censos (INEC- ECUADOR) at the
web page www.inec.gob.ec: http://www.
ecuadorencifras.gob.ec/estadisticas-de-camas-yegresos-hospitalarios-bases-de-datos/; RDACAA
Data is available from the RDACAA database
accessible at the Ecuadorian Ministry of Public
Health.
Funding: This work was financially supported by
the Universidad de las AmeÂricas Quito grant
number (VET.MC.17.03). Funders had no role in
Conclusions
The burden of acute respiratory infections remained steady during the analyzed period.
Evidence-based prevention and control policies to tackle acute respiratory infections in
Ecuador should focus on the population at extreme ages of life.
study design, data collection and analysis, decision
to publish, or preparation of the manuscript.
Introduction
Respiratory infections are the greatest single contributor to the overall burden of disease in the
world[
1,2
]. Despite a small decrease of 3.2%, the global burden of lower respiratory infections
continues to be the third leading cause of death in 2015 worldwide[3]. According to the Global
Burden of Disease study lower respiratory infections are the leading cause of Years of Life Lost
(YLL) in Ecuador [
3
]. The Ecuadorian National Institute for Statistics and Censuses (INEC)
reported Influenza and pneumonia (ICD-10 codes J09-J18) as the fifth leading cause of death
[
4
]. Burden estimation of pneumonia and other acute respiratory infections remains an urgent
need in order to evaluate their impact and to assess the cost-effectiveness of public health
interventions[
5
].
In Ecuador, as in other tropical latitudes, the absence of a well-defined flu season, the
coexistence of other respiratory viruses and the variability of clinical presentation of acute
respiratory infections, predispose health services to underestimate the burden of acute respiratory
infections (ARI)[
6
]. Despite pre-pandemic reports of viral activity in Ecuador[
7
] and viral
identification through notification to the Ministry of Health of Ecuador, available studies do
not allow the estimation of the burden of influenza or Influenza-like Illnesses (ILI) in Ecuador.
Same as in ILI, definition and diagnosis of other viruses and bacterial infections is not strong
enough to characterize the attribution of burden. Considering these limitations, we propose
the estimation of burden of acute respiratory disease in order to assess an approximation of
the impact of this set of diseases using national databases available during the 2011±2015
period.
Materials and methods
Geographical location and study population
Ecuador is a Latin American country located in the Pacific coast of South America. This
country has a continental territory and the Galapagos Islands. The continental territory is divided
by the Andes Mountains in three different regions: coastal, highlands and Amazonia. In
general, there is little seasonal temperature variations through the year in each region, but there is
a wide variation of climate characteristics between regions. The coast and the Amazonia are
characterized as tropical rainforest and highlands as temperate regions.
INEC estimated that Ecuador population for 2016 was 16.5 million people (49.5% male and
50.5% female). Most people live in urban areas (63.3%). INEC estimated regional distribution
of population as follows: Coastal 49.6%, highlands 44.7%, Amazonia 5.3% and 0.2% Galapagos
Islands. 0.2% population live in non-delimited areas. Thirty percent of people are less than 15
years old. Ecuador has the highest population density in the region with an average of 54.5
habitants per km2.[
8
]
Sources of information
We use available data from the national registries of deaths, hospital discharges, and
ambulatory consultations published by the INEC, and the Ecuadorian Ministry of Health in the 2011±
2015 period[
4
]. Cases and deaths registered were grouped according to their ICD-10 code
(Table 1) into the following diagnostic groups: Acute upper respiratory infections (J00-J06),
Influenza and pneumonia (J09-J18), Bronchitis and other acute lower respiratory infections
(J20-J22)[
9
].
Outpatient data were obtained from the Automated Daily Register of Ambulatory
Consultations (Registro Diario Automatizado de Consultas y Atenciones AmbulatoriasÐRDACAA)
provided by the Ministry of Health since year 2013. Based on this information, an outpatient
2 / 12
to inpatient ratio was estimated. This ratio allowed extrapolation from hospitalized cases to
total cases for years 2011 and 2012[
10
]. Information from ambulatory consultations, hospital
discharges, and deaths registries was tabulated by ICD code, sex and age group to calculate
incidence and mortality rates. Incidence and mortality rates per 1000 population were
calculated with a level of confidence of 95%.
Ethical approval was not required for this study. Information used in this analysis came
from freely available public databases published by the INEC and the Ecuadorian Ministry of
Health. Anonymity of clinical records is guaranteed by legal mandate and their use is
authorized for research and academic purposes while keeping confidentiality (ªREGLAMENTO DE
INFORMACION CONFIDENCIAL EN SISTEMA NACIONAL DE SALUDº available at:
http://instituciones.msp.gob.ec/cz6/images/lotaip/Enero2015/Acuerdo%20Ministerial%
205216.pdf).
Estimation of the burden of disease
The burden of disease attributable to acute respiratory infections for each year of the study
period, was measured in disability-adjusted life years (DALYs) as summary measure following
the methods described by Murray et al. [
11
]. Calculations were made using the ªDALYº
package for R [
12
].
3 / 12
DALYs are the sum of years lived with disability (YLDs) and years of life lost due to
premature mortality (YLLs). Following an incidence perspective, YLDs were estimated as the product
of the number of incident cases times the duration of disease symptoms in years, and the
disability weight attributed to the disease.
To estimate the disease duration, we calculated the average hospital length of stay based on
the reports obtained from the databases and from available literature [
13,14
]. 0.0192 years for
J00-J06, 0.041 years for J20-J22 and 0.0274 years for J09-J018, J85-J86.
Disability weights (DW) for each disease group were assigned accordingly to the estimates
by the Global Burden of Disease 2013 study: mild acute episode DW = 0.006 (95% CI 0.002±
0.012) for ICD-10 codes J00-J06; moderate acute episode DW = 0.051 (95% CI 0.032±0.074)
for ICD-10 codes J20-J22; and severe acute episode DW = 0.133 (95% CI 0.088±0.190) for
ICD-10 codes J09-J18, J85-J86[
15
].
YLLs were estimated as the product of the number of deaths and the residual life
expectancy at the age of death. To estimate residual life expectancy we used the Coale and Demeny
model life table West, with a life expectancy at birth of 80 years for males and 82.5 years for
females[
11
]. YLLs were also calculated using the WHO Life tables 2011±2015 estimates for
Ecuador[
16
]. A time discount rate of 3% without age weighting was used in the calculations
[
11
].
The economic burden was estimated following the human capital method[
17
], as the
indirect costs generated by the productivity losses, valued in current US dollars, due to the
absenteeism of the economically active patient, or the productivity loss of one caregiver in the case
of minors and the elderly. Indirect costs included the loss of resources due to morbidity and
mortality, considering the minimum monthly wage of a formal worker in Ecuador valued in
US$ 516.25 [
18
]. It was not possible to perform a claims-based examination of health care
costs because of the lack of electronic health records and billing systems in the public sector.
Statistical analysis
The statistical differences for mortality rates between age groups were assessed using the
Poisson test. The differences of the contribution of DALYs by age group were assessed using the
proportion test with the ªBonferroniº correction for multiple comparisons. To assess the
seasonality of events, a regression analysis using the ªtslmº function of the ªforecastº package in R
version 3.3.3 was used. Statistical significance was assumed for all the analysis with a p-value
inferior to 0.05.
Results
Over the 5-year period studied there were a total of 14.84 million cases of acute respiratory
infections with 17 757 deaths reported (0.12%). About 17 241 deaths (97.2%) were attributed
to influenza or pneumonia (ICD-10 codes J09-J18). Significant differences were observed
among the mortality rates across all age categories (p<0.00005). Mortality rates during the
studied period were higher in the over60 years-old age group being 6 to 9 times higher than in
the population under 5 years-old, the other age categories had statistically significant lower
rates (p<0.00005).
Seasonality was observed for hospitalizations from August to January (p = 0.000059) and
for mortality cases from September to February (p = 0.048).
There were 258 261 hospital discharges during the study period, 74.15% due to ICD-10
codes J09-J18, J85-J86. Incidence of acute upper respiratory infections (J00-J06) was higher in
the age group under 5 years-old in all the periods studied. Incidence rates per 1000 population
4 / 12
ICD-10, International Statistical Classification of Diseases and Related Health Problems 10th Revision; J00-J06, Acute upper respiratory infections; J09-J18, Influenza
and pneumonia; J20-J22, Other acute lower respiratory infections.
for ambulatory and hospitalized cases are presented in Tables 2 and 3 respectively, mortality
rates per 1000 population are presented in Table 4.
The yearly burden of disease ranged between 99864 (97672±102093) to 119300 (116897±
121712) DALYs equivalent to 6.39 (6.36±6.43) to 7.56 (7.52±7.61) DALYs per 1000 population
(Table 5). In every year studied 99% of DALYs were attributed to YLLs mainly due to
premature mortality by influenza and pneumonia in population under 5 years-old and over 60
yearsold (Table 6). There were no significant differences in the burden of disease estimations with
Coale and Demeny model life table West and WHO 2011±2015 life tables estimates for
Ecuador.
The average annual losses due to indirect cost in current US dollars equals US$152.16
million (±19.6 millions), equivalent to 0.164% of the Gross Domestic Product of Ecuador. Total
productivity losses in the five-year period studied accounts US$760.8 million. (Table 7)
5 / 12
ICD-10, International Statistical Classification of Diseases and Related Health Problems 10th Revision; J00-J06, Acute upper respiratory infections; J09-J18, Influenza
and pneumonia; J20-J22, Other acute lower respiratory infections; J85-J86, Suppurative and necrotic conditions of lower respiratory tract.
Discussion
Most of the available estimations of burden of pneumonia, acute respiratory diseases and other
infectious diseases, have been done through methodologies based on analysis of systematic
reviews, expert opinion, literature reviews and data extrapolation [19±21]. In 2013, Savy et al.
performed a systematic review to estimate the burden of influenza in Latin America and the
Caribbean. This group stated that pneumonia and influenza related deaths are most common
in population age groups under5 years-old and over 60-years-old, reporting that influenza and
pneumonia deaths in Ecuador were the highest in Latin America (14.4%) for the year 2003 in
children under 5 years-old. Finally, they stated that underreporting and scarce information
impede accurate estimation of impact of influenza in the region of Latin America and the
Caribbean [
22
].
6 / 12
7 / 12
Available data about DALYs in Ecuador for upper and lower respiratory infections in 2015
obtained from the Institute for Health Metrics and Evaluation Global Health Data Exchange
web page (IHME) [
23
] reports 184 053.03 DALYs (95% CI 213 970.98±162 755.42). The
differences obtained between the results reported in the present study (104 103 DALY) and the
estimations obtained by the IHME could be attributed to methodological differences. The
overlapping clinical syndromes caused by the etiologic agents of acute respiratory infections
make it difficult to assign a specific etiology based on the clinical presentations. Our approach
using both hospitalized cases and ambulatory cases databases provide an estimation of burden
without adjustment for other non-specific causes of morbidity and mortality. Thus, obtaining
reliable population-based estimates for disease burden of respiratory infections remains a
challenge.
The two highest drivers of the burden of acute respiratory infections are premature deaths
in the populations over 60 years-old and under 5 years-old, which produces a high number of
YLL. This ªU-shapedº distribution of death rates by age group is concordant with the situation
reported by Lara-Oliveros et al. [
24
]in a low income district in Bogota, Colombia, and also
compares to reports from Brazil and India [
25,26
]. Worldwide, acute respiratory infections
were responsible for about 1.9 million pediatric deaths in 2000 [
27,28
]. According the Forum
of International Respiratory Diseases, more than 4 million deaths annually are produced by
acute respiratory infections in developing countries. This forum attributes risk factors as living
in crowded conditions, malnutrition, lack of immunization, HIV and exposure to tobacco or
indoor smoke [
1,2
]. Public health decisions concerning acute respiratory diseases should be
focused in these two age groups. While partial seasonal patterns in mortality and
hospitalizations were found in this study, seasonal effect and molecular characterization of circulating
viruses in ambulatory consultations should be investigated in further research. A recent study
on the etiology of severe pneumonia in Ecuadorian children described the association of
respiratory syncytial virus, metapneumovirus, and adenovirus with severe infections [29]. In
temperate regions, public health decisions about influenza immunization are defined upon viral
characterizations for each region. In tropical countries it is not clear if it is necessary to follow
8 / 12
a seasonal pattern or not. New evidence about recommendations of vaccine use in tropical
regions could be implemented in Ecuador [30±32]. Seasonal influenza vaccine, conjugate
pneumococcal vaccine and Pentavalent Vaccine (DPT-HepB-Hib) were administered
regularly in 2007 as part of the national vaccination program [
33
]. Currently, the Ecuadorian
vaccination scheme includes programmed immunization with these agents [
34
]. According to
official reports, vaccine coverage has declined since 2014 until 2017 in all age groups. For
instance, reported coverage in children from 6 to 11 months of age fell from 79% in the 2014±
2015 period, to 46% in the 2016±2017 period. For children of 1 to 3 years-old, coverage
declined from 93 to 65% and in pregnant women, it declined from 72 to 43%. In people older
than 65 years-old, it declined from 100% of coverage for 2014±15 to 82% in the 2015±16
period. There is no data for this specific age group for the 2016±17 period [
8
]. A limitation in
this study was that data before 2007 is not available to compare the impact of these
interventions in matters of disease burden.
Availability of public databases allows prompt use of data to assess epidemiological
variables in population and decisions in public health. Existing data of acute upper respiratory
infections are always underestimated because of nonspecific clinical presentation and a
perceived lack of need of medical attention for a benign illness.
Acute respiratory infections are directly linked to prescribed or auto-prescribed
consumption of drugs. The demand for generic and brand name drugs is highly driven by non-steroidal
anti-inflammatory drugs (NSAIDs), especially by those recommended for the symptoms of
cold and flu [
2
]. In a short unpublished analysis, during 2012 to 2014, Ecuador spent more
than 29.5 million USD in flu and cold medication (NSAIDs + nasal decongestant +
antihistamine) representing more than 6.4 million units sold during those years. The consumption of
treatment drugs is determined essentially by 1) doctors' prescription given in ambulatory
attention, 2) hospitalization and rehabilitation, and/or by 3) the user
(auto-medicationÐauto-prescription [
35
]. Access to these drugs is also regulated by the economic status of the population,
with the poorer group spending the most in out of pocket expenses [
36
]. In further research,
direct and indirect costs related with acute respiratory infections should be estimated.
Direct costs could not be estimated in this study because the health system in Ecuador does
not have a billing system or register of direct expenses generated by medical consultation.
However, our estimation of indirect costs could be an initial approach to the economic impact
that acute respiratory infections produces in the economy of Ecuador.
Conclusions
Periodic analyses of the burden of diseases can stimulate the implementation of
evidencebased prevention and control policies to tackle acute respiratory infections in Ecuador
specially influenza and pneumonia cases at extreme ages of life. Implementation of methodic
processes of estimation should be encouraged in multiple scenarios.
National immunization programs are the first intervention that must be maintained in terms
of coverage and quality. Activity surveillance and virological characterization of respiratory
viruses especially at primary care settings need to be implemented to complement information
of acute respiratory infections. Finally, widespread awareness in health services in the country
about impact, management and report of acute respiratory infectious should be permanent.
Acknowledgments
We would like to thank The Ministry of Public Health of Ecuador, The National Sub
secretariat of Public Health Surveillance and the National Direction of Statistics and Analysis of Health
Metrics for helping with the availability of the data used in this study.
9 / 12
Author Contributions
Conceptualization: Wilson Chicaiza-Ayala, Aquiles R. HenrÂõquez-Trujillo, Esteban
Ortiz
Prado, Marco Coral-Almeida.
Data curation: Wilson Chicaiza-Ayala, Aquiles R. HenrÂõquez-Trujillo, Esteban Ortiz-Prado.
Investigation: Wilson Chicaiza-Ayala, Aquiles R. HenrÂõquez-Trujillo, Esteban Ortiz-Prado,
Marco Coral-Almeida.
Methodology: Wilson Chicaiza-Ayala, Aquiles R. HenrÂõquez-Trujillo, Marco Coral-Almeida.
Project administration: Marco Coral-Almeida.
Software: Wilson Chicaiza-Ayala, Aquiles R. HenrÂõquez-Trujillo, Marco Coral-Almeida.
Supervision: Wilson Chicaiza-Ayala, Aquiles R. HenrÂõquez-Trujillo, Richard W. Douce,
Marco Coral-Almeida.
Validation: Wilson Chicaiza-Ayala, Richard W. Douce.
Writing ± original draft: Wilson Chicaiza-Ayala, Aquiles R. HenrÂõquez-Trujillo, Esteban
Ortiz-Prado, Richard W. Douce, Marco Coral-Almeida.
Writing ± review & editing: Wilson Chicaiza-Ayala, Aquiles R. HenrÂõquez-Trujillo, Esteban
Ortiz-Prado, Richard W. Douce, Marco Coral-Almeida.
10 / 12
11 / 12
1. Ferkol T , Schraufnagel D . The Global Burden of Respiratory Disease. Ann Am Thorac Soc [Internet] . 2014 Mar [cited 2017 Jan 25 ]; 11 ( 3 ): 404 ± 6 . Available from: http://www.atsjournals.org/doi/abs/10.1513/ AnnalsATS.201311- 405PS
2. Forum of International Respiratory Societies. Respiratory diseases in the world. Realities of TodayÐ Opportunities for Tomorrow [Internet] . Sheffield; 2013 [cited 2017 Jan 25 ]. http://www.theunion.org/ what-we-do/publications/technical/english/FIRS_report_for_web.pdf
3. Wang H , Naghavi M , Allen C , Barber RM , Bhutta ZA , Carter A , et al. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980±2015: a systematic analysis for the Global Burden of Disease Study 2015 . Lancet. 2016 ; 388 ( 10053 ): 1459 ± 544 . https://doi.org/10.1016/S0140- 6736 ( 16 ) 31012 - 1 PMID: 27733281
4. Instituto Nacional de EstadÂõstica y Censos [Internet]. [cited 2017 Feb 21 ]. http://www.ecuadorencifras. gob.ec/estadisticas/
5. Mulholland K. Perspectives on the burden of pneumonia in children . Vaccine . 2007 ; 25 : 2394 ±7. https:// doi.org/10.1016/j.vaccine. 2006 . 09 .007 PMID: 17064827
6. Viboud C , Alonso WJ , Simonsen L . Influenza in tropical regions . PLoS Med [Internet]. 2006 Apr [cited 2010 Jul 29 ] ; 3(4):e89 . Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid= 1391975&tool=pmcentrez&rendertype=abstract
7. Douce RW , Aleman W , Chicaiza W , Madrid C , Sovero M , Delgado F , et al. Sentinel surveillance of influenza-like-illness in two cities of the tropical country of Ecuador: 2006±2010 . Aguilar PV ., editor. PLoS One [Internet] . 2011 Jan 24 [cited 2014 Jun 11 ] ; 6(8):e22206 . Available from: http://dx.plos. org/10 . 1371/journal.pone.0022206
8. Ministerio de Salud PuÂblica del Ecuador , SecretarÂõa Nacional de PlanificacioÂn y Desarrollo, OrganizacioÂn Panamericana de la Salud, World Health Organization. EvaluacioÂn de la Estrategia Nacional de Inmunizaciones [Internet]. Quito; 2017 . http://www.paho.org/ecu/index.php ?option=com_ docman&view=download&category_slug=inmunizaciones&alias=673-evaluacion-de-la-estrategianacional- de- inmunizaciones-ecuador-2017 &Itemid=599
9. International Statistical Classification of Diseases and Related Health Problems 10th Revision [Internet] . Vol. 2017 . World Health Organization; 2016 . http://apps.who.int/classifications/icd10/browse/ 2016/en
10. Undurraga EA , Halasa YA , Shepard DS . Use of Expansion Factors to Estimate the Burden of Dengue in Southeast Asia: A Systematic Analysis . PLoS Negl Trop Dis . 2013 ; 7 ( 2 ):e2056. https://doi.org/10. 1371/journal.pntd. 0002056 PMID: 23437407
11. Murray CJ . Quantifying the burden of disease: the technical basis for disability-adjusted life years . Bull World Heal Organ [Internet] . 1994 ; 72 ( 3 ): 429 ± 45 . Available from: https://www.ncbi.nlm.nih.gov/ pubmed/8062401
12. Devleesschauwer B , McDonald S , Haagsma J , Praet N , Havelaar A , Speybroeck N. DALY: The DALY CalculatorÐA GUI for stochastic DALY calculation in R [Internet] . R package . 2014 . http://cran.rproject. org/package=DALY
13. National Institute for Health and Clinical Excellence. Respiratory Tract InfectionsÐAntibiotic Prescribing: Prescribing of antibiotics for self-limiting respiratory tract infections in adults and children in primary care [Internet] . Vol. 69 ,. 2008 . 1 ±240 p. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21698847
14. Thompson M , Vodicka TA , Blair PS , Buckley DI , Heneghan C , Hay AD . Duration of symptoms of respiratory tract infections in children: systematic review . BMJ [Internet] . 2013 Dec 11 ; 347(dec11 1):f7027± f7027 . Available from: http://www.bmj.com/cgi/doi/10.1136/bmj.f7027
15. Salomon JA , Haagsma JA , Davis A , de Noordhout CM , Polinder S , Havelaar AH , et al. Disability weights for the Global Burden of Disease 2013 study. Lancet Glob Heal [Internet] . 2015 ; 3 ( 11 ):e712± 23 . Available from: https://www.ncbi.nlm.nih.gov/pubmed/26475018
16. Repository GHO data. Life tables by country: Ecuador [Internet] . World Health Organization; 2016 . http://apps.who.int/gho/data/view.main. 60490 ?lang=en
17. Jo C . Cost-of-illness studies: concepts, scopes, and methods . Clin Mol Hepatol [Internet]. 2014 Dec [cited 2017 Dec 3 ]; 20 ( 4 ): 327 ± 37 . Available from: http://www.ncbi.nlm.nih.gov/pubmed/25548737
18. Ministerio del Trabajo de Ecuador . Acuerdo Ministerial No. MDT-2016-0300 [Internet]. Ecuador; 2016 p. 2 . http://www.trabajo.gob.ec/wp-content/uploads/downloads/2017/01/ AM-SBU-MDT- 2016-0300.pdf
19. McDonald SA , Devleesschauwer B , Wallinga J. The impact of individual-level heterogeneity on estimated infectious disease burden: a simulation study . Popul Health Metr [Internet] . 2016 ; 14 : 1 ± 9 . Available from: http://myaccess.library.utoronto.ca/login?url=http://search.ebscohost.com/login.aspx ? direct=true&db=rzh&AN=120270123&site=ehost-live
20. Reed C , Chaves SS , Kirley PD , Emerson R , Aragon D , Hancock EB , et al. Estimating influenza disease burden from population-based surveillance data in the United States . PLoS One . 2015 ; 10 ( 3 ).
21. Tromme I , Legrand C , Devleesschauwer B , Leiter U , Suciu S , Eggermont A , et al. Melanoma burden by melanoma stage: Assessment through a disease transition model . Eur J Cancer . 2016 ; 53 : 33 ± 41 . https://doi.org/10.1016/j.ejca. 2015 . 09 .016 PMID: 26693897
22. Savy V , Ciapponi A , Bardach A , Glujovsky D , Aruj P , Mazzoni A , et al. Burden of influenza in Latin America and the Caribbean: a systematic review and meta-analysis . Influenza Other Respi Viruses [Internet] . 2013 Nov [cited 2017 Feb 2]; 7 ( 6 ): 1017 ± 32 . Available from: http://doi.wiley. com/10 .1111/irv. 12036
23. Institute for Health Metrics and Evaluation . GBD Results Tool | GHDx [Internet]. [cited 2017 Feb 22 ]. http://ghdx.healthdata.org/gbd-results-tool
24. Lara Oliveros CA , De Graeve D , Franco F , Daza SP . Disease burden and medical cost-analysis of Acute Respiratory Infections in a low-income district of Bogota . Rev Salud PuÂblica [Internet] . 2016 Oct 7 [cited 2018 Mar 31 ]; 18 ( 4 ): 568 . Available from: http://www.revistas.unal.edu.co/index.php/ revsaludpublica/article/view/45485
25. Peasah SK , Purakayastha DR , Koul PA , Dawood FS , Saha S , Amarchand R , et al. The cost of acute respiratory infections in Northern India: a multi-site study . BMC Public Health [Internet] . 2015 Apr 7 [cited 2018 Mar 31 ]; 15 : 330 . Available from: http://www.ncbi.nlm.nih.gov/pubmed/25880910
26. de Corrêa RA , de JoseÂ BPS , Malta DC , de Passos VM A , FrancËa EB , Teixeira RA , et al. Carga de doencËa por infeccËões do trato respiratoÂrio inferior no Brasil , 1990 a 2015: estimativas do estudo Global Burden of Disease 2015. Rev Bras Epidemiol [Internet] . 2017 May [cited 2018 Mar 31]; 20(suppl 1): 171 ± 81 . Available from: http://www.scielo.br/scielo.php ?script=sci_arttext&pid=S1415- 790X2017000500171&lng=pt&tlng=pt
27. Williams BG , Gouws E , Boschi-Pinto C , Bryce J , Dye C . Estimates of world-wide distribution of child deaths from acute respiratory infections . Lancet Infect Dis [Internet] . 2002 Jan [cited 2017 Feb 6]; 2 ( 1 ): 25 ± 32 . Available from: http://www.ncbi.nlm.nih.gov/pubmed/11892493
28. Bryce J , Boschi-Pinto C , Shibuya K , Black RE , WHO Child Health Epidemiology Reference Group. WHO estimates of the causes of death in children . Lancet [Internet] . 2005 Mar [cited 2017 Feb 6 ]; 365 ( 9465 ): 1147 ± 52 . Available from: http://www.ncbi.nlm.nih.gov/pubmed/15794969
29. Jonnalagadda S , RodrÂõguez O , Estrella B , Sabin LL , SempeÂrtegui F , Hamer DH . Etiology of severe pneumonia in Ecuadorian children . PLoS One [Internet] . 2017 [cited 2017 Jul 21 ]; 12 ( 2 ):e0171687. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28182741
30. Hirve S , Newman LP , Paget J , Azziz-Baumgartner E , Fitzner J , Bhat N , et al. Influenza Seasonality in the Tropics and SubtropicsÐWhen to Vaccinate?
31. Saha S , Chadha M , Al Mamun A , Rahman M , Sturm-Ramirez K , Chittaganpitch M , et al. Influenza seasonality and vaccination timing in tropical and subtropical areas of southern and south-eastern Asia . Bull World Heal Organ [Internet] . 2014 ; 92 : 318 ± 30 . Available from: http://dx.doi.org/10.2471/BLT.13. 124412
32. Saha S , Chadha M , Shu Y , Lijie W , Chittaganpitch M , Waicharoen S , et al. Divergent seasonal patterns of influenza types A and B across latitude gradient in Tropical Asia . Influenza Other Respi Viruses . 2016 ;
33. Ministerio de Salud PuÂblica del Ecuador . Lineamientos TeÂcnicos y Operativos para la VacunacioÂn contra la Influenza Estacional y Neumococo [Internet] . Ecuador; 2007 . https://aplicaciones.msp.gob.ec/ salud/archivosdigitales/documentosDirecciones/dnn/archivos/LINEAMIENTOS T EÂCNICOS OPERATIVOS PARA LA VACUNACI OÂN CONTRA LA INFLUENZA ESTACIONAL Y NEUMOCOCO DE.pdf
34. Ministerio de Salud PuÂblica del Ecuador. Esquema de VacunacioÂn Familiar / Ecuador 2015 [Internet]. 2015 [cited 2017 Feb 23 ]. http://instituciones.msp.gob.ec/images/Documentos/Ministerio/Esquema_ de_vacunacion_ 2015 _ 2 .pdf
35. Ortiz-Prado E , Galarza C , Cornejo LeoÂn F , Ponce J . Access to drugs and the situation of the pharmaceutical market in Ecuador . Rev Panam Salud PuÂblica . 2014 ; 36 ( 1 ): 57 ± 62 . PMID: 25211679
36. Ortiz-Prado E , Ponce J , Cornejo-Leon F , Stewart-Ibarra AM , HenrÂõquez Trujillo R , EspÂõn E , et al. Analysis of Health and Drug Access Associated with the Purchasing Power of the Ecuadorian Population . Glob J Health Sci [Internet] . 2017 [cited 2017 Feb 22 ]; 9 ( 1 ). Available from: http://dx.doi.org/10.5539/ gjhs.v9n1p201